Biology subjects

Matsui, K.

Publications and source records attributed to Matsui, K..

18 recordsLinked to original sources

bioRxiv2026

Real-time ultrafast holography of focused ultrasound wave fields using an ultrasound scanner

Acoustic pressure field measurements are required for marketing clearance of medical ultrasound instruments, but the gold standard method, hydrophone scanning, is time consuming. The objective of this work was to develop an ultrafast holographic method for real-time imaging of focused ultrasound fields. The technique is based on parallel acquisition with a sensor array, and FUS field reconstruction based on time reversal assuming a homogeneous lossless medium. The geometric characteristics of the sensor to enable accurate reconstruction were evaluated through numerical modelling. A practical example involving a commercially-available 128-element linear-array ultrasound imaging probe is presented. Finally, preliminary experiments were conducted on in-vitro soft tissues to validate the concept of simultaneous dual-mode imaging, combining conventional B-mode tissue imaging with FUS field holography. In modelling of ideal sensor characteristics (2D matrix; intercepted energy > 99%), parallel holography allowed reconstructing wave fields with excellent agreement with the Rayleigh Integral reference (errors << 0.01%). Successfully experimental demonstration of real-time ultrafast wave field holography was achieved with the commercial imaging probe (7-10% error in the -6dB focus vs hydrophone measurements, acquisition time: 100 microseconds, display rate: 15 frames/s), despite a suboptimal intercepted energy (44%). Real-time dual-mode imaging of continuous wave fields allowed targeting localized tissues regions, while holographic movies highlighted the propagation of transient waves. Overall, real-time ultrafast holography offers a practical way to perform metrology and guidance of ultrasonic devices, by visualising waves fields typically used for ultrasound imaging, or those used during thermal or non-thermal ultrasound therapy.

bioengineering↗

bioRxiv2026

Embodied Emergence of Temporal Complexity in Finger Tapping: Synaptic and Dopaminergic Control in Cortico-Basal Ganglia Loops

Finger tapping is a crucial clinical window into the brain's motor integrity, particularly in Parkinson's disease (PD). Beyond mere rhythmicity, healthy motor output exhibits long-range correlations (LRCs)--a hallmark of temporal complexity and physiological adaptability. However, how this fractal structure emerges from the interplay between neural circuits and physical body dynamics, and why it collapses under dopamine depletion, remains elusive. Here, we present an embodied computational model integrating the cortico-basal ganglia-thalamocortical (CBGT) loop with a physical finger model under intermittent control. We demonstrate that LRC is not stochastic noise, but emerges from the interaction between physical finger dynamics and intermittent, sensory-driven action selection. Our simulations reveal that while unbiased action selection yields random variability, a sensory-driven striatal bias generates robust LRC, demonstrating that motor complexity can be actively driven by neural "synaptic bias" rather than passive body mechanics. Crucially, simulating PD pathology via dopamine reduction disrupts this bias, leading to a loss of complexity and white-noise transitions that recapitulate a key qualitative feature of the fractal breakdown observed in PD. By bridging neuromodulation, biomechanical execution, and macroscopic behavior, this work provides a mechanistic framework for embodied neural information processing and offers a potential digital-twin platform for objective biomonitoring in neurodegenerative disorders.

neuroscience↗

bioRxiv2026

Neryl diphosphate-derived monoterpene biosynthesis via a biosynthetic gene cluster in the liverwort Marchantia polymorpha

Monoterpenes (C10) are a large group of specialized metabolites important for plant interactions with the environment. Their biosynthesis is well understood in seed plants, where geranyl diphosphate serves as the canonical substrate, but knowledge of monoterpene biosynthesis outside seed plants remains very limited. Here, we report neryl diphosphate (NPP)-derived monoterpene biosynthesis via a biosynthetic gene cluster in the liverwort Marchantia polymorpha. MpMTPSL2, a microbial-type terpene synthase, converts NPP into -phellandrene and D-limonene in vitro. CRISPR knockout lines showed reduced production of both monoterpenes, providing direct genetic evidence for its in planta function. MpCPT5, a cis-prenyltransferase (CPT) family member identified through co-expression with MpMTPSL2, was confirmed to encode NPP synthase, as its knockout plants abolished -phellandrene and D-limonene production. Subcellular localization analyses in protoplasts and stable transgenic plants demonstrated that both MpCPT5 and MpMTPSL2 localize to plastids, co-localizing across all cell types with markedly stronger signals in non-green plastids of oil-body cells. Consistent with this, expression of both genes under their respective promoters was nearly abolished in oil-body-deficient mutants and strongly upregulated in a gain-of-function line for oil-body formation. MpMTPSL2 and MpCPT5 are physically linked through a shared bidirectional promoter that drives their coexpression specific to oil body cells, forming a unique biosynthetic gene cluster whose coordinated expression is maintained by PRC2-mediated H3K27me3 repression. Phylogenetic analysis implies that NPP synthases in M. polymorpha and in flowering plants evolved independently from their respective long-chain CPT ancestors. These findings provide new insights into the mechanisms and evolution of monoterpene biosynthesis in non-seed plants. Significance statementMonoterpenes are a diverse group of specialized metabolites produced widely among land plants, yet our understanding of their biosynthesis outside seed plants remains limited. Here we report that in the liverwort Marchantia polymorpha, the non-canonical substrate neryl diphosphate is used for monoterpene biosynthesis. The functions of the monoterpene synthase gene MpMTPSL2 and the neryl diphosphate synthase gene MpCPT5 were demonstrated through CRISPR knockouts. These two genes are physically linked and share a bidirectional promoter. Promoter assays show both genes function in plastids within oil-body cells, revealing cell-type specificity. These findings shew new light on the mechanisms and evolution of monoterpene biosynthesis in non-seed plants.

plant biology↗

bioRxiv2026

LsBADH1 is responsible for sweet fragrance in lettuce (Lactuca sativa L.) through 2-acetyl-1-pyrroline biosynthesis

HighlightThe sweet fragrance of lettuce was attributed, for the first time, to the synthesis of 2-acetyl-1-pyrroline caused by a deficiency in the betaine aldehyde dehydrogenase gene. Fragrance is among the most valuable traits of high-quality crops and influences consumer preferences. Although 2-acetyl-1-pyrroline (2AP) is a key component of fragrant cultivars in several crops, its genetic mechanism in lettuce (Lactuca sativa L.) remains poorly understood. The betaine aldehyde dehydrogenase (BADH) gene has been identified as causative for 2AP-derived fragrance in rice and soybean cultivars. Hence, we conducted a linkage analysis using an F2 population derived from a cross between Kukichisya (fragrant) and Rennet (non-fragrant) for three candidate genes of BADH orthologs in the lettuce genome. Analysis linked LOC111877932 located in LG4 to the fragrance trait, and it was designated LsBADH1. Comparison among Kukichisya, Salinas, and candidate BADH of sunflower (Helianthus annuus L.) revealed three non-synonymous single-nucleotide polymorphisms (nsSNPs) in exons 1, 2, and 9, and suggested that nsSNP in exon 9 was strongly correlated with fragrance in Kukichisya. A premature stop codon introduced in exon 5 of LsBADH1 using Target-AID base-editing technology resulted in truncated BADH1 and higher 2AP levels. Our results indicated that LsBADH1 is responsible for the 2AP-derived fragrance. Our findings can be applied to select cultivars based on a novel concept for the cooking process, providing a transformative platform to breed fragrant lettuce as a high-value-added product.

genetics↗

bioRxiv2026

eSkip2 prioritizes exon-skipping antisense oligonucleotide target regions across exon--intron contexts

Exon-skipping antisense oligonucleotides (ASOs) can restore productive transcripts, but identifying effective binding regions remains difficult because splicing regulation extends across exons, introns and splice junctions. Here we develop eSkip2, a genome-informed framework that ranks target regions within a unified exon-intron sequence context. eSkip2 combines a genome-pretrained sequence model with ASO-induced exon-skipping data and single-nucleotide-variant splicing perturbations, followed by target-locus adaptation that requires no experimental ASO labels from the locus being designed. Across benchmarks comprising canonical exons and pseudoexons, multiple cell types and chemistries, and exonic, intronic and exon-intron-spanning targets, eSkip2 prioritized active regions and showed a higher median AUROC than applicable exon-restricted models. Prospective application to the combinatorial design of dual-targeting ASOs for DMD exon 46 enriched active candidates near the top of the ranking: the two most active new ASOs ranked within the top three and produced dose-dependent dystrophin restoration in patient-derived cells. These results support eSkip2 as a practical first-pass strategy for reducing experimental search space in exon-skipping ASO discovery.

bioinformatics↗

bioRxiv2026

Digital twins of upright stance reveal mechanistic bifurcations underlying Parkinsonian sway phenotypes

How the central nervous system maintains upright stance--and why this capability collapses in Parkinsons disease (PD)--remains a fundamental open question in computational neuroscience. A primary barrier is a severe topological degeneracy between observable sway kinematics (z-space) and latent neural control policies (-space), causing radically distinct control strategies to mask as identical sway patterns. Here, we establish a dynamical digital twin framework bridging empirical sway time series with mechanistic physical models. Assimilating a large cohort (N = 1, 038) into an intermittent control model via Bayesian inference, we construct a bidirectional mapping (z {leftrightarrow} ) that unmasks these hidden dynamics. We prove that healthy stance is universally governed by flexible intermittent control near an optimal intermittency ratio ({rho} {approx} 0.5), whereas PD progression reflects a structural regression toward rigid continuous control ({rho} [->] 1). Crucially, parameter topology in -space reveals that neural control policies reside on a folded low-dimensional manifold separated by a distinct parameter gap; attractor bifurcation analysis demonstrates that a catastrophic tipping point is embedded within this void, proving that parkinsonian postural breakdown is driven by a discontinuous dynamical phase transition rather than continuous control decay. By unmasking hidden disease severity beneath degenerate sway phenotypes, our framework reframes parkinsonian motor failure as an attractor bifurcation on a neural control manifold, providing a modern computational realization of the classical "dynamical disease" paradigm. SignificancePostural collapse in Parkinsons disease presents a profound neurobiological paradox: cellular degeneration progresses continuously over decades, yet clinical motor failure strikes as a sudden, catastrophic collapse. We resolve this paradox by demonstrating that motor breakdown is not a passive decay of control resources, but a discontinuous dynamical phase transition (attractor bifurcation) triggered when underlying neural control policies cross a latent parameter gap. By unmasking "phenotypic degeneracy"--where radically different neural control strategies produce identical body sway--our digital twin framework redefines neurodegenerative motor failure as a qualitative regime shift in complex control dynamics, offering a universal paradigm for predicting catastrophic transitions in neurological disorders.

neuroscience↗

bioRxiv2026

A macrocyclic peptide-based fusion inhibitor targeting SARS-CoV-2 Spike S2 subunit

Continuous emergence of SARS-CoV-2 variants carrying mutations in Spike presents a significant challenge for durable antiviral agents. Here we screen for random 13-amino acid non-mimetic macrocyclic peptides that bind to Spike and identify PA-001 that inhibits SARS-CoV-2 infection with high potency at 0.23-2.9 nM as 50% inhibitory concentration (IC50). PA-001 bound to Spike S2 subunit and inhibited the membrane fusion during virus entry. Through drug-resistant selection, we revealed that PA-001 targeted the fusion peptide proximal region (FPPR) in S2, which has not been recognized as a drug target to date. Consistent with its highly conserved amino acid sequences beyond strains, PA-001 exhibited broad antiviral activity against all tested SARS-CoV-2 variants, in contrast to clinically-approved S1-targeting antibodies that lost activity to Omicron variants. PA-001 suppressed SARS-CoV-2 propagation and disease progression in mouse- and hamster-infection models, both by administration prophylactically and therapeutically. Combination therapy with remdesivir further enhanced antiviral profiles. In clinical phase-I trial, PA-001 was well-tolerated and showed high systemic exposure, with 4,300-10,300-fold concentration of IC50 as maximum plasma concentration by single administration to healthy volunteers. These evidence propose FPPR as an unexpected antiviral drug target accessible by macrocyclic peptides and identify PA-001 as a potent anti-SARS-CoV-2 fusion inhibitor.

microbiology↗

bioRxiv2025

Hox - Meis-relayed topographical genetic switch underlies cardiopharyngeal neural crest diversification, revealed by multimodal analysis

Neural crest cells (NCCs) are multipotent migratory cells essential for cardiac development, yet the lineage trajectories and gene regulatory networks (GRNs) underlying their differentiation in the cardiopharyngeal region remain unclear. Here, we integrate single-cell RNA-seq, spatial transcriptomics, and multiomic analyses to construct a comprehensive map of NCC lineages in developing mouse cardiopharyngeal tissues. We identify a transition from Hox-positive pharyngeal NCCs to Hox-negative intracardiac populations associated with the outflow tract cushion, accompanied by a shift in Meis transcription factor binding and GRN architecture. By contrast, NCCs forming the aorticopulmonary septum and great vessel smooth muscle retain distinct Hox-codes. A Meis2-Sox9-Scx GRN defines a skeletogenic progenitor-like intermediate state that gives rise to coronary artery smooth muscle and semilunar valves. Our findings suggest that the loss of Hox-dependent regional identity enables pharyngeal NCCs to acquire new fates upon entering the cardiac cushion, providing insight into the developmental origins of coronary and valvular calcification.

developmental biology↗

bioRxiv2025

ABCG transporters are involved in the accumulation of specialized metabolites in the oil bodies of Marchantia polymorpha

Bioactive specialized metabolites (SMs) are synthesized and sequestered in specific cellular compartments or organelles as a self-defense strategy against their intrinsic toxicity. Liverwort-specific oil bodies accumulate large amounts of SMs and contribute to chemical defense; however, the molecular mechanisms underlying SM sequestration in oil bodies remain largely unknown. Therefore, in this study, we focused on MpABCG1 and MpABCG36, which are ATP-binding cassette (ABC) protein family members localized to the oil bodies of liverwort Marchantia polymorpha. Sesquiterpene (thujopsene, chamigrene, and himachalane) accumulation was reduced in the Mpabcg1 and Mpabcg36 loss-of-function mutants. Notably, levels of the bisbibenzyls, marchantins C and A, were predominantly reduced in Mpabcg1, but not in Mpabcg36. Although the Mpabcg1 mutant formed a number of oil bodies labeled with mCitrine- MpSYP12B (oil body membrane marker) comparable to that of the wild-type, the number of oil bodies stained with BODIPY 493/503, which has an affinity for lipophilic SMs, was reduced. This finding suggests that MpABCG1 and MpABCG36 mutations affect SM accumulation in the oil body but have little impact on oil body formation. Overall, our results highlight the involvement of MpABCG1 and MpABCG36 in the accumulation of SMs and/or their precursors in liverwort oil bodies.

plant biology↗

bioRxiv2025

Searching for Acrolein-Scavenging Compounds in Plants: Isoalliin from Onion as an Excellent Scavenger

Reactive carbonyl species (RCS), such as acrolein (Acr), are generated through the degradation of lipid peroxides and exert cytotoxic effects. To identify natural RCS scavengers, we examined 80% ethanol extracts from 46 angiosperm species for Acr-trapping activity using an HPLC-based assay. Strong activities were observed in several taxa, including garlic, spinach, avocado, broccoli, and lotus. In garlic, the active metabolite was identified as S-allyl-L-cysteine sulfoxide (alliin), a characteristic Allium amino acid. Alliin and its S-(1E)-propenyl and S-methyl derivatives (isoalliin and methiin, respectively) trapped up to two Acr molecules at the amino group and exhibited higher activities than known scavengers such as carnosine and epigallocatechin gallate. These findings highlight S-alk(en)yl-L-cysteine sulfoxides as potent secondary antioxidants and suggest that structurally diverse RCS scavengers remain to be discovered in plants.

plant biology↗

bioRxiv2024

Descending locus coeruleus noradrenergic signaling to spinal astrocyte subset is required for stress-induced pain facilitation

It is known that stress powerfully alters pain, but its underlying mechanisms remain elusive. Here, we identified a circuit, locus coeruleus descending noradrenergic neurons projecting to the spinal dorsal horn (LC[->]SDH-NA neurons), that is activated by acute exposure to restraint stress and is required for stress-induced mechanical pain hypersensitivity in mice. Interestingly, the primary target of spinal NA released from descending LC[->]SDH-NAergic terminals causing the stress-induced pain hypersensitivity was 1A-adrenaline receptors (1ARs) in Hes5-positive (Hes5+) astrocytes located in the SDH, an astrocyte subset that has an ability to induce pain sensitization. Furthermore, activation of Hes5+ astrocytes reduced activity of SDH-inhibitory neurons (SDH-INs) that have an inhibitory role in pain processing. This astrocytic reduction of IN activity was canceled by an A1-adenosine receptor (A1R)-knockdown in SDH-INs, and the A1R-knockdown suppressed pain hypersensitivity caused by acute restraint stress. Therefore, our findings suggest that LC[->]SDH-NA neuronal signaling to Hes5+ SDH astrocytes and subsequent astrocytic reduction of SDH-IN activity are essential for mechanical pain facilitation caused by stress.

neuroscience↗

bioRxiv2024

Fetal Kidney Transplantation for In Utero Fetuses

Potter sequence, characterized by bilateral renal agenesis, oligohydramnios, and consequent pulmonary hypoplasia, presents a significant challenge in the management of affected neonates. Due to their prematurity and associated abdominal complications, these infants often fail to reach a stage where dialysis can be safely initiated and sustained, leading to an exceedingly high mortality rate. Therefore, there is hopeful anticipation that interventions serving as a bridge to achieve a state where dialysis can be safely performed will markedly improve life expectancy. We have developed a unique approach of "transplantation of fetal kidneys from a different species during the fetal period" as a bridge therapy until stable dialysis therapy can be implemented. This is a new concept of fetal therapy, targeting the fetus in utero and utilizing fetal kidneys of an appropriate size for transplantation. In this study, we first validated the approach using allogeneic transplantation. Fetal kidneys with bladders from GFP-expressing rats (gestational age 14.0-16.5 days) were transplanted subcutaneously into allogeneic rat fetuses in utero (gestational age 18.0-18.5 days) using a special needle transuterinally, and live pups were successfully obtained. The transplanted fetal kidneys with bladders were confirmed to have urine production capability. By periodic aspiration of the subcutaneous urinary cyst after birth, urine produced by the transplanted fetal kidney was successfully drained outside the body for an extended period (up to 150 days). Biochemical tests confirmed the solute removal capacity of the transplanted fetal kidney. Furthermore, despite allogeneic transplantation, long-term urine production was sustained without the use of immunosuppressants, confirming that organ transplantation into fetuses is associated with lower rejection compared to adult transplantation. Next, xenotransplantation was performed. When GFP-expressing mouse fetal kidneys (gestational age 13.0-13.5 days) were transplanted into rat fetuses in utero, maturation of renal tissue structures was confirmed even in the interspecies setting.

bioengineering↗

bioRxiv2024

Generation of human-pig chimeric renal organoids using iPSC technology

The potential of using porcine organs and human induced pluripotent stem cell (iPSC)-derived organoids as alternative organs for human transplantation has garnered growing attention. However, both approaches still face technological challenges. Interspecies chimeric organ production using human iPSCs is expected to be another promising approach that addresses the challenges associated with organ production. Our research group successfully generated human-mouse chimeric renal organoids by utilizing human iPSC-derived nephron progenitor cells (NPCs) and fetal mouse kidneys. However, the current technology has limited engraftment and development capabilities for human NPCs, and there have been no reports of generating interspecies chimeric renal organoids in larger animals, limited only to rodents. Therefore, in this study, we embarked on the production of human-pig chimeric renal organoids using the pig kidney, which is considered the most promising source of organs for interspecies transplantation to humans. To construct a human-pig chimeric renal organoid culture system, we first modified the existing human-mouse chimeric renal organoid culture system and developed a method that enables the survival and continued renal development of both species. This method was found to be applicable to porcine fetal kidney cells, and ultimately, we successfully produced human-pig chimeric renal organoids. Furthermore, this culture method can also be applied to the generation of human interspecies chimeric kidneys for future clinical applications. The findings of this study serve as a foundational technology that will greatly accelerate future research in humanized pig kidney production for clinical purposes, and are also expected to be used as an evaluation technique to ensure the quality of human NPCs for xenotransplantation.

bioengineering↗

bioRxiv2024

Advancing marker-gene-based methods for prokaryote-mediated multifunctional redundancy: exploring random and nonrandom extinctions in a watershed

Multifunctional redundancy, the extent of loss in multiple ecosystem functions with decreasing biodiversity, stands as a crucial index for evaluating ecosystem resilience to environmental changes. We aimed to refine a marker-gene-based methodology for quantifying multifunctional redundancy in prokaryotic communities. Using PICRUSt2, we predicted KEGG orthologs (KOs) for each Amplicon Sequence Variant (ASV), assessed community-wide KO richness, and validated predictions against experimentally quantified phenotypic multifunctionality. Additionally, we introduced a refined regression on ASV richness-KO richness curves, providing a reliable estimate of the power-law exponent within computational time constraints, serving as the multifunctional redundancy index. Incorporating various non-random extinction scenarios alongside a random one allowed us to quantify estimate variations between scenarios, providing conservative estimates of multifunctional redundancy. Applied to Lake Biwa and four of its inlet rivers, the refined methodology unveiled spatio-temporal variations in multifunctional redundancy. Our analysis demonstrated lower redundancy in Lake Biwa compared to rivers, aiding in prioritizing conservation targets and inferring distinct community assembly processes. Future directions include a deeper exploration of KO composition information for detailed multifunctionality quantification and the refinement of extinction scenarios. This study demonstrates the promising integration of bioinformatic functional prediction and modeling biodiversity loss, offering a valuable tool for effective ecosystem management.

ecology↗

bioRxiv2023

Plastic vasomotion entrainment

The presence of global synchronization of vasomotion induced by oscillating visual stimuli was identified in the mouse brain. Endogenous autofluorescence was used and the vessel "shadow" was quantified to evaluate the magnitude of the frequency-locked vasomotion. This method allows vasomotion to be easily quantified in non-transgenic wild-type mice using either the wide-field macro-zoom microscopy or the deep-brain fiber photometry methods. Vertical stripes horizontally oscillating at a low temporal frequency (0.25 Hz) were presented to the awake mouse and oscillatory vasomotion locked to the temporal frequency of the visual stimulation was induced not only in the primary visual cortex but across a wide surface area of the cortex and the cerebellum. The visually induced vasomotion adapted to a wide range of stimulation parameters. Repeated trials of the visual stimulus presentations resulted in the entrainment of the amplitude of the vasomotion. Horizontally oscillating visual stimulus is known to induce horizontal optokinetic response (HOKR). The amplitude of the eye movement is known to increase with repeated training sessions and the flocculus region of the cerebellum is known to be essential for this learning to occur. Here, we show a strong correlation between the average HOKR performance gain and the vasomotion entrainment magnitude in the cerebellar flocculus. Therefore, the plasticity of vasomotion and neuronal circuits appeared to occur in parallel. Efficient energy delivery by the entrained vasomotion may contribute to meeting the energy demand for increased coordinated neuronal activity and the subsequent neuronal circuit reorganization.

neuroscience↗

bioRxiv2022

Cardiac neural crest lineage diversity and underlying gene regulatory networks revealed by multimodal analysis

Neural crest cells (NCCs), a multipotent stem cell population, contribute to cardiac development as a source of the outflow septum, vascular smooth muscle and semilunar valves. However, genetic programs underlying lineage diversification of cardiac NCCs remain largely unknown. Using single-cell (sc) and spatial transcriptomics, we demonstrate multiple NCC subpopulations with distinct gene expression signatures; smooth muscle(-like), non-muscle mesenchymal, and Schwann cell progenitor/melanoblast-like cells. Integrative scRNA-seq and scATAC-seq analyses predict lineage trajectories starting from immature NCCs, which bifurcate into smooth muscle(-like) and non-muscle mesenchymal lineages in association with hierarchical transcription factor networks. Combinatory analyses with Cre-mediated genetic lineage tracing characterize intermediate NCCs at the bifurcation as Sox9+/Scx+ tendon and cartilage progenitor-like cells with genetic programs, some of which are common to skeletal tissues whereas others are unique to cardiac NCCs. These findings provide a basis for understanding the roles of NCCs in cardiac development and pathogenesis particularly associated with calcification.

developmental biology↗

bioRxiv2020

Region-specific and state-dependent astrocyte Ca2+ dynamics during the sleep-wake cycle in mice

Neural activity is diverse, and varies depending on brain regions and sleep/wakefulness states. However, whether astrocyte activity differs between sleep/wakefulness states, and whether there are differences in astrocyte activity among brain regions remain poorly understood. In this study, we recorded astrocyte intracellular calcium (Ca2+) concentrations of mice during sleep/wakefulness states in the cortex, hippocampus, hypothalamus, cerebellum, and pons using fiber photometry. For this purpose, male transgenic mice in which their astrocytes specifically express the genetically encoded ratiometric Ca2+ sensor YCnano50 were used. We demonstrated that Ca2+ levels in astrocytes significantly decrease during Rapid Eye Movement (REM) sleep and increase after the onset of wakefulness. In contrast, differences in Ca2+ levels during non-Rapid Eye Movement (NREM) sleep were observed among different brain regions, and no significant decrease was observed in the hypothalamus and pons. Further analyses focusing on the transition between sleep/wakefulness states and correlation analysis with episode duration of REM showed that Ca2+ dynamics differed among brain regions, suggesting the existence of several clusters. To quantify region-specific Ca2+ dynamics, principal component analysis was performed to uncover three clusters; i.e., the first comprised the cortex and hippocampus, the second comprised the cerebellum, and the third comprised the hypothalamus and pons. Our study demonstrated that astrocyte Ca2+ levels change substantially according to sleep/wakefulness states. These changes were generally consistent, unlike neural activity. However, we also clarified that Ca2+ dynamics varies depending on the brain region, implying that astrocytes may play various physiological roles in sleep. Significance statementSleep is an instinctive behavior of many organisms. In the previous five decades, the mechanism of the neural circuits controlling sleep/wakefulness states and the neural activities associated with sleep/wakefulness states in various brain regions have been elucidated. However, whether astrocytes, which are a type of glial cell, change their activity during different sleep/wakefulness states is poorly understood. Here, we demonstrated that dynamic changes in intracellular Ca2+ concentrations occur in the cortex, hippocampus, hypothalamus, cerebellum, and pons of genetically modified mice during natural sleep. Further analyses demonstrated that Ca2+ dynamics slightly differ among different brain regions, implying that the physiological roles of astrocytes in sleep/wakefulness might vary depending on the brain region.

neuroscience↗

bioRxiv2016

Empirical Bayes estimation of semi-parametric hierarchical mixture models for unbiased characterization of polygenic disease architectures

Genome-wide association studies (GWAS) suggest that the genetic architecture of complex diseases consists of unexpectedly numerous variants with small effect sizes. However, the polygenic architectures of many diseases have not been well characterized due to lack of simple and fast methods for unbiased estimation of the underlying proportion of disease-associated variants and their effect-size distribution. Applying empirical Bayes estimation of semi-parametric hierarchical mixture models to GWAS summary statistics, we confirmed that schizophrenia was extremely polygenic ([~] 40% risk variants of independent genome-wide SNPs, most within odds ratio (OR)=1.03), whereas rheumatoid arthritis was less polygenic ([~] 4 to 8% risk variants, significant portion reaching OR=1.05 to 1.1). For rheumatoid arthritis, stratified estimations revealed that expression quantitative loci in blood explained large genetic variance, and low- and high-frequency derived alleles were prone to be risk and protective, respectively, suggesting a predominance of deleterious-risk and advantageous-protective mutation. Despite genetic correlation, effect-size distributions for schizophrenia and bipolar disorder differed across allele frequency. These analyses distinguished disease polygenic architectures and provided clues for etiological differences in complex diseases.

genomics↗